Various complexes of monodentate and bidentate ligands with technetium have been made and studied. These complexes generally were made for use in studies to determine the various oxidation states of technetium and for other research regarding the structure of such complexes and metal-coordination chemistry. Such studies have been reported in, for instance, Chemistry and Industry, pp. 347-8 Mar. 26, 1960); J. Inorg. Nucl. Chem., Vol. 28, pp 2293-96 (1966); Aust. J. Chem., 23, pp 453-61 (1970); Inorganic Chem., vol. 16, No. 5, pp. 1041-48 (1977), J. Inorg. Nucl. Chem., Vol. 39, pp. 1090-92 (1977); and J. C. S. Dalton, pp. 125-30 (1976).
Recently, in a presentation to the American Pharmaceutical Association, E. A. Deutsch disclosed that certain complexes of DIARS, i.e. ##STR1## and Tc-99m, and certain complexes of DMPE, i.e. (CH.sub.3).sub.2 PCH.sub.2 CH.sub.2 P(CH.sub.3).sub.2, and Tc-99m may be useful as radiodiagnostic agents for myocardial or hepatobiliary imaging. [.sup.99m Tc-(DMPE).sub.2 Cl.sub.2 ].sup.+ and [.sup.99m Tc-(DIARS).sub.2 Br.sub.2 ].sup.+ were prepared by Deutsch by heating in an open flask a reaction mixture containing the appropriate hydrogen halide in aqueous alcohol solution, .sup.99m Tc-sodium pertechnetate, and ortho-phenylenebis(dimethylarsine), i.e. DIARS, or bis-(1,2-dimethylphosphino)ethane, i.e. DMPE. The reaction was reported to take about 30 minutes. The labelled complex was then purified by chromatographic methods involving ion exchange columns.
The labelled complex produced according to the procedure of Deutsch has several practical disadvantages. The procedure requires handling several ingredients including an organic solvent to make the reaction mixture and then purifying the resulting radiolabelled complex by chromatography. Each of these handling steps can contaminate the system and final product. The purification step further requires additional time for preparation of the final product. These steps require a stilled technician and are performed at the site of use, just prior to use. Thus, a complex, time consuming chemical preparation is required during which sterility of ingredients and containers is difficult to maintain. Thus, to assure freedom from contamination, a final sterilization step is required, which further adds to preparation time. Because Tc-99m has a short half-life, lengthy preparation methods are undesirable. Thus, the complexity of the preparation, both with regard to maintaining sterile conditions and to purification of the .sup.99m Tc-labelled complex make the Deutsch procedure undesirable.
It would be highly desirable to have a sterilized kit with all the necessary materials prepared by the manufacturer, to which only the Tc-99m need be added at the site of use to produce the desired labelled complex directly in high enough yield to obviate the need for purification. It would also be desirable for the kit materials to be in a closed container or vial, pre-sterilized, so that the only step to be performed at the site of use would be the addition of the radionuclide. To increase stability and shelf-life of the kit, it would be highly desirable that the materials be readily lyophilized, preferably from an aqueous solution.
By achieving the desirable features outlined above, a convenient-to-use heart imaging radiopharmaceutical agent would be provided that is capable of concentrating in healthy heart tissue to provide a negative image of an infarct, or damaged or ischemic tissue.
A copending application, Ser. No. 311,770, filed Oct. 15, 1981 in the name of Vinayakam Subramanyam, which is hereby incorporated by reference, describes an acid salt of a mono or polydentate ligand that is water soluble, stable in a lyophilized state, and is capable of binding with Tc-99m to form a cationic complex. The acid salt may be generally represented by the formula: ##STR2## wherein: i is an integer from 1 to 6;
R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups, and R plus R.sup.i may be taken together to form a cyclic compound or separately to form a linear compound; PA0 Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5 and Y.sup.6 are independently selected from substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; PA0 A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 and A.sup.6 are the same or different neutral donor atoms, each having a free-electron pair available for accepting a proton to provide a charged ligand or for complexing with Tc-99m or Tc-99 to form a cationic complex; PA0 Z is preferably a parenterally acceptable anion; PA0 k.sub.1, k.sub.2, k.sub.3, k.sub.4, k.sub.5 and k.sub.6 are each independently zero or one; PA0 n.sub.1, n.sub.2, n.sub.3, n.sub.4, n.sub.5 and n.sub.6 are independently 0 or 1; and n.sub.7 and n.sub.8 are integers from 1 to 6 where ##EQU1## and the charge represented by n.sub.8 Z is equal in magnitude and opposite in sign to +n.sub.7 ; or ##STR3## wherein: R, R' and R" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; PA0 A, A' and A" are independently selected from the group of neutral donor atoms having a pair of electrons available for accepting a proton to provide a charged ligand or for complexing with Tc-99m or Tc-99 to form a cationic complex; PA0 j, j' and j" are independently 0 or 1; PA0 n, n' and n" are independently the integer 1 or 2; PA0 Z is the same as defined above PA0 n.sub.9 and n.sub.10 are integers selected from 1 to about 3, where n.sub.9 =j+j'+j" and the charge represented by n.sub.10 Z is equal in magnitude and opposite in sign to +n.sub.9. PA0 R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups, and R plus R.sup.i may be taken together to form a cyclic compound or separately to form a linear compound; PA0 Y.sup.1, Y.sup.2, Y.sup.3, Y.sup.4, Y.sup.5 and Y.sup.6 are independently selected from substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocycloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; PA0 A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 and A.sup.6 are the same or different neutral donor atoms, each having a free-electron pair available for complexing with Tc-99m or Tc-99 to form a cationic complex; and PA0 k.sub.1, k.sub.2, k.sub.3, k.sub.4, k.sub.5 and k.sub.6 are each independently zero or one; ##STR5## wherein: R, R' and R" are independently selected from hydrogen or substituted or usubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; PA0 A, A' and A" are independently selected from the group of neutral donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; and PA0 n, n' and n" are independently the integer 1 or 2; or ##STR6## wherein R, R', R" and R'" are independently selected from hydrogen or substituted or unsubstituted alkyl, aryl, alkylaryl, arylalkyl, monocylcloalkyl, polycycloalkyl, heterocyclic and carbocyclic groups; PA0 A', A" and A'" are independently selected from the group of neutral donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 to form a cationic complex; PA0 B is an atom selected from the group of neutral donor atoms having a pair of electrons available for complexing with Tc-99m or Tc-99 or from the elements listed in Group IV A of the periodic table (i.e. C, Si, Ge, Sn, and Pb); PA0 m is 0 is 1; PA0 n', n" and n'" are independently the integer 1 or 2; PA0 wherein the technetium coordinate bond with said bidentate accelerator ligand is weaker than the technetium coordinate bond with said target-seeking ligand. PA0 1,2-bis(dimethylphosphino)ethane, PA0 1,2-bis(di(trifluoromethyl)phosphino)ethane, PA0 1,2-bis(dimethylphosphino)-1,1-difluoroethane, PA0 1,2-bis(dimethylphosphino)-1-fluoroethane, PA0 1,2-bis(dimethylphosphino)propane, PA0 1,2-bis(di(trifluoromethyl)phosphino)-1,1,2,2-tetrafluoroethane, PA0 1,2-bis(di(trifluoromethyl)phosphino)propane, PA0 2,3-bis(di(trifluoromethyl)phosphino)butane, PA0 1,2-bis(di(trifluoromethyl)phosphino)butane, PA0 1,3-bis(dimethylphosphino)butane, PA0 1,3-bis(dimethylphosphino)propane, PA0 1,3-bis(di(trifluoromethyl)phosphino)propane, PA0 1,2-bis(dimethylphosphino)-1,1-dichloro-2,2-difluoroethane, and similar compounds wherein the phosphorus is replaced by nitrogen, arsenic, sulfur, oxygen, selenium, tellurium, or any other atom having a free electron pair, and the like.
These acid salts are normally solid compounds, water-soluble, readily lyophilized, and capable of reducing pertechnetate and binding with technetium to form stable cationic complexes.
Cationic technetium complexes of these acid salts, useful for radiodiagnostic treatments, are prepared for mixing the acid salt and .sup.99m Tc-pertechnetate in an aqueous or alcoholic solution and heating the mixture to form the cationic complex. Preferably, the ligand is provided as a lyophilized ligand acid salt as described by V. Subramanyam in copending application Ser. No. 311,770 and is contained in a sealed, sterilized vial prior to adding the pertechnetate. The pertechnetate solution can then be injected into the vial under aspetic conditions to maintain sterility. To obtain high yields, the vial is generally heated and maintained at an elevated temperature for sufficient time to form a complex of the ligand with technetium. The vial should preferably be heated to at least 80.degree. C. for a suitable length of time, i.e. about 30 minutes or more at 80.degree. C. Preferably, the vial is heated to 100.degree. C. or more, and more preferably to a temperature in the range of from about 130.degree. C. to about 150.degree. C. At about 150.degree. C., the reaction can be completed in about five to ten minutes, depending upon the choice and concentrations of the reactants. After cooling, the resulting radiopharmaceutical preparation may be adjusted for pH and is ready for use. Typically, when the pH is adjusted, it is adjusted into the range of from about 4.0 to about 9.0, and preferably to physiological pH.
It is desirable to obtain high yields of the cationic technetium complexes for radiodiagnostic uses in one step without the need for purification of the labelled compound. It is also desirable to obtain these high yields using temperatures of 100.degree. C. or less because constant temperature water baths are readily available in clinical laboratories.